Bryson Alexander, Petrou Steven
Ion Channels and Disease Group, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.
Praxis Precision Medicines, Inc., Cambridge, MA, United States.
Front Neurol. 2023 Apr 17;14:1173460. doi: 10.3389/fneur.2023.1173460. eCollection 2023.
The gene is strongly associated with epilepsy and plays a central role for supporting cortical excitation-inhibition balance through the expression of Na1.1 within inhibitory interneurons. The phenotype of disorders has been conceptualized as driven primarily by impaired interneuron function that predisposes to disinhibition and cortical hyperexcitability. However, recent studies have identified gain-of-function variants associated with epilepsy, and the presence of cellular and synaptic changes in mouse models that point toward homeostatic adaptations and complex network remodeling. These findings highlight the need to understand microcircuit-scale dysfunction in disorders to contextualize genetic and cellular disease mechanisms. Targeting the restoration of microcircuit properties may be a fruitful strategy for the development of novel therapies.
该基因与癫痫密切相关，通过抑制性中间神经元中Na1.1的表达，在维持皮质兴奋 - 抑制平衡中发挥核心作用。疾病的表型主要被认为是由中间神经元功能受损导致的，这种受损易引发去抑制和皮质兴奋性过高。然而，最近的研究已经确定了与癫痫相关的功能获得性变异，以及小鼠模型中细胞和突触变化的存在，这些变化指向稳态适应和复杂的网络重塑。这些发现凸显了理解疾病中微电路水平功能障碍以阐明遗传和细胞疾病机制的必要性。针对恢复微电路特性可能是开发新疗法的有效策略。
